The congenital long QT syndrome (LQTS) is a clinically heterogenous group of inherited cardiac channelopathies characterized by prolongation of the electrocardiographic QTc interval and an increased propensity towards syncope, cardiac arrest, and sudden cardiac death (SCD) resulting from a unique form of polymorphic ventricular tachycardia (VT) known as torsades de pointer (TdP).
There are currently 13 putative subtypes of LQTS. The most common subtypes are LQT1 (˜45%), LQT2 (˜45%), and LQT3 (7%). Other forms of LQTS (LQT4-10) are very rare and account for <3% of all LQTS. LQT1 and LQT2 are caused by loss of function mutations in the genes encoding the potassium (K+) channels that underlie the delayed rectifier K+ currents, IKs and IKr, respectively. LQT3 is caused by gain-of-function mutations in SCN5A, the gene that encodes the cardiac voltage-gated sodium (Na+) channel, Nav1.5, resulting in an increase in the late Na+ current (INa).
The mutant gene causes abnormal channels to be formed and as these channels do not function properly, the electrical recovery of the heart takes longer, which manifests itself as a prolonged QT interval. For example, an inherited deletion of amino-acid residues 1505-1507 (KPQ) in the cardiac Na+ channel, encoded by SCN5A, causes the severe autosomal dominant LQT3 syndrome associated with fatal ventricular arrhythmias. Fatal arrhythmias occur in 64% of LQT3 patients during sleep or rest, presumably because excess late Na+ current abnormally prolongs repolarization, particularly at low heart rates and thereby favors development of early afterdepolarizations (EADs) and ectopic beats. Preferential slowing of repolarization in the mid-myocardium might further enhance transmural dispersion of repolarization and cause unidirectional block and reentrant arrhythmias. In another 16% of LQT3 patients, fatal cardiac events are triggered by exercise or emotion.
To date, approximately 75 distinct mutations in SCN5A have been linked to LQT3. In most of these mutations, incomplete or slow inactivation of sodium channels induces a persistent or “late” Na+ current. At the myocyte level, the increased late Na+ current prolongs the APD, and promotes the formation of EADs and DADs, which are cellular triggers for malignant arrhythmias. These molecular defects and altered kinetics in the sodium channel gating mechanism are characterized at the organ level by prolongation of the QTc interval. In patients with LQT3, QTc prolongation represents the electrocardiographic hallmark of prolonged ventricular repolarization due to increased late Na+ current. Finally, at the whole organism level, the prolonged QT interval and an increased dispersion of repolarization times among ventricular myocytes provide the sine qua non for the initiation of TdP, a type of polymorphic VT that can lead to syncope (if transient and self-terminating) or SCD (if sustained and degenerating to VF).
Several drugs that are currently used to treat cardiovascular, neuronal, infectious diseases or other conditions are associated with increased risk of prolonging the QT interval, which is considered as a substrate for the life-threatening ventricular tachycardia, Torsade de Pointes (TdP). Therefore, drug-induced QT interval prolongation is generally used as a proxy for an increased risk of TdP, i.e. risk of SCD. Drug-induced QT-interval prolongation is most often due to a concentration-dependent inhibition of the delayed-rectifier K+ current encoded by human-ether-a-go-go (hERG) gene. Examples of drugs that causes QT interval prolongation include but not limited to anti-arrhythmics, antipsychotics, anti-depressants, anti-viral agents, antibiotics, and other medications. A list of drugs that have been shown to prolong the QT interval is available at https://www.crediblemeds.org/everyone/composite-list-all-qtdrugs/.